The main purpose of this proposal is to evaluate a sequential chemopreventive therapy regimen on dysplastic bronchial epithelium and correlate its effect on histopathology and several biomarkers. We plan to recruit 225 heavy smokers (greater than 30 pack-years) without evidence of overt lung cancer over a two year period. A newly developed fluorescence bronchoscopic method that can detect bronchial dysplasia with a sensitivity that is more than twofold better than conventional white-light bronchoscopy will be used to localize potential dysplastic bronchial lesions for biopsy for pathological confirmation. Eighty subjects with biopsy proven bronchial dysplasia will be enrolled into a randomized clinical trial of retinol (Aquasol A) 50,000 IU/day versus placebo for 6 months. Changes in histopathology grade on a lesion by lesion basis will be used as the primary end-point for the intervention. This will be achieved by fluorescence bronchoscopy and precise re-biopsy of all areas found to have dysplasia at baseline as well as any new lesions appearing at the end of 6 months of study medication. Subjects with reversion of dysplasia will have a third bronchoscopy one year off medication to determine the long term outcome. Those who have stable, new or progressive lesions after 6 months of retino/placebo will enter into a Phase II toxicity and feasibility trial of anetholatrithione (Sialor) 25 mg po tid for 6 months. Repeat bronchial biopsy will be performed at the end of 6 months to assess the outcome. The usefulness of other biomarkers in bronchial biopsies such as retinoid acid receptor (RAR-p), LOH in 3p, 5q, 9p, p53, or rb, telomerase expression and quantitative morphometry (which includes DNA content and nuclear textural features) will be examined as potential intermediate end-point(s) for outcome assessment which may not be completely reflected by changes in histopathology alone. To explore the use of a non-invasive method to identify, in high risk groups, individuals harboring pre-neoplastic lung lesion(s), a three-dab pooled sputum cytology specimen will be obtained from all 225 subjects prior to the baseline bronchoscopy. The presence of Progression (Malignancy) Associated Changes (PACs) will be examined using an automated quantitative image cytometer. The results will be correlated with the presence/absence of bronchial dysplasia on bronchoscopy to determine if PACs can be used for risk assessment. In addition, sputum specimens will be obtained monthly in the subset of subjects taking study medication to determine if PACs can be used to monitor the response to chemopreventive therapy. The study will provide new information on the use of novel biomarkers for identifying individuals harboring preneoplastic bronchial lesions and on the use of these biomarkers as intermediate end-points for assessing the effect of chemoprevention.